Mibefradil- and omega-conotoxin GVIA-induced inhibition of noradrenaline release from the sympathetic nerves of the human heart.
Segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to determine the effects of mibefradil, omega-conotoxin (omega-CTx) GVIA and nifedipine on tritium overflow evoked by transmural electrical stimulation. Mibefradil (which predominantly blocks T-type, and at lower potency also N-type, Ca2+ channels) at concentrations of 0.3-3 microM reduced the electrically evoked tritium overflow in a reversible and concentration-dependent manner (IC50%: 1 microM), whereas 0.1-10 microM nifedipine (a selective blocker of L-type channels) was ineffective. The evoked tritium overflow was almost abolished by 0.2 microM omega-CTx GVIA (a selective blocker of N-type channels). It is concluded that noradrenaline release from cardiac sympathetic nerves is triggered by Ca2+-influx via N-type, but not L-type, Ca2+ channels and that the inhibitory effect of mibefradil at clinically relevant concentrations on noradrenaline release is probably due to its blocking action on N-type Ca2+ channels. This property of mibefradil is unique among the therapeutically applied Ca2+ channel blockers and may contribute to the slight negative chronotropic effect of the drug in vivo.
Göthert
M
M
Institut für Pharmakologie und Toxikologie, Rheinische Friedrich Wilhelms-Universität Bonn, Germany.
Molderings
G J
GJ
D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005260:Female; D005728:Ganglia, Sympathetic / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D020866:omega-Conotoxin GVIA
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D010455:Peptides; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D020866:omega-Conotoxin GVIA; D009638:Norepinephrine